Pilot Project Abstract - Kroenke, Christopher, PhD

The objective of the proposed studies is to undertake an integrated neuroimaging, cellular, and molecular approach to define mechanisms of age-related cognitive decline (ARCD). ARCD is a complex convergent phenotype that describes declining cognitive function from a variety of causes as people age, and it is a major source of disability and reduced autonomy that will challenge our health care system and tax our economy in the coming decades. Though the primary focus of dementia research has been to understand mechanisms of gray matter damage, increasingly mounting evidence supports a role of white matter damage in ARCD. In particular, neuroimaging-based studies have identified a role of vascular cognitive impairment in ARCD. We propose to examine human autopsy brains from the Adult Changes in Thought (ACT) study to characterize the biochemical and cellular-level basis of these neuroimaging-based findings. We will utilize the OHSU ultra-high field 12 Tesla MRI system to identify abnormalities in white matter in this population. We will then employ immunohistochemical markers specific to the oligodendrocyte lineage, other glia, and axons to define cellular mechanisms related to myelination disturbances in the MR-defined lesions. Both experimental approaches will be referenced to biochemical assessments of oxidative damage within adjacent brain regions characterized through the ACT study. Through this combined effort we will generate a unique and highly complementary resource of frontal lobe white matter from a human population-based study of brain aging and cognitive impairment.